You are on page 1of 49

WHO/HIV/2005.

02

INTERIM WHO
CLINICAL STAGING OF HIV/AIDS
AND
HIV/AIDS CASE DEFINITIONS FOR
SURVEILLANCE

AFRICAN REGION
WHO/HIV/2005.02

INTERIM WHO
CLINICAL STAGING OF HIV/AIDS
AND
HIV/AIDS CASE DEFINITIONS FOR
SURVEILLANCE

AFRICAN REGION

I
© World Health Organization 2005

All rights reserved. Publications of the World Health Organization can be obtained
from Marketing and Dissemination, World Health Organization, 20 Avenue Appia,
1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857;
email: bookorders@who.int). Requests for permission to reproduce or translate
WHO publications – whether for sale or for noncommercial distribution – should be
addressed to Marketing and Dissemination, at the above address (fax: +41 22 791 4806;
email: permissions@who.int).

The designations employed and the presentation of the material in this publication do
not imply the expression of any opinion whatsoever on the part of the World Health
Organization concerning the legal status of any country, territory, city or area or of its
authorities, or concerning the delimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply
that they are endorsed or recommended by the World Health Organization in preference
to others of a similar nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by WHO to verify the information contained
in this publication. However, the published material is being distributed without warranty
of any kind, either express or implied. The responsibility for the interpretation and use of
the material lies with the reader. In no event shall the World Health Organization be liable
for damages arising from its use.

Printed in

II INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
III
CONTENTS

Acronyms and Abbreviations __________________________________________________ V

Executive summary __________________________________________________________1

Background ________________________________________________________________2
9 Revised WHO clinical staging of HIV/AIDS for adults and adolescents _____________________5
16 Revised WHO clinical staging of HIV/AIDS for infants and children _______________________ 11
29
41 Recommendations for implementation ___________________________________________18

Annex 1. WHO clinical staging for adults and adolescents: presumptive and definitive criteria for
recognizing HIV/AIDS-related clinical events _______________________________________20

Annex 2. WHO clinical staging for infants and children: presumptive and definitive criteria for
recognizing HIV/AIDS-related clinical events _______________________________________30

Key References ____________________________________________________________42

IV INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
ACRONYMS AND ABBREVIATIONS

AFB acid-fast bacilli


AIDS acquired immunodeficiency syndrome
ART antiretroviral therapy
ARV antiretroviral medicine
BAL bronchoalveolar lavage
CD4 human T helper cells expressing CD4 antigen (T helper cell)
CDC Centers for Disease Control and Prevention (USA)
CMV cytomegalovirus
CNS central nervous system
CRAG cryptococcal antigen
CSF cerebrospinal fluid
CT computed tomography
CXR chest X-ray
DNA deoxyribonucleic acid
HIV human immunodeficiency virus
HSV herpes simplex virus
IMCI integrated management of childhood illness
IRS immune restoration syndrome
JC Jacob Creutzfeldt (Virus)
LGE linear gingival erythema
LIP lymphoid interstitial pneumonitis
LP lumbar puncture
LRTI lower respiratory tract infection
LTB laryngotracheal bronchitis
MOT mycobacteria other than tuberculosis
MRI magnetic resonance imaging
NAT nucleic acid testing
P24 a soluble antigen produced by HIV
PCP pneumocystis pneumonia
PCR polymerase chain reaction
PGL persistent generalized lymphadenopathy
PLWHA people living with HIV/AIDS
PML progressive multifocal leukoencephalopathy
RF rectal fistula
RVF rectovaginal fistula
RNA ribonucleic acid
SD standard deviation
TB tuberculosis
TLC total lymphocyte count
URTI upper respiratory tract infection
WHO World Health Organization
ZN Ziehl-Neelsen (staining method)

V
EXECUTIVE SUMMARY

W
ith a view to facilitating the scale-up of access to antiretroviral therapy
(ART) in the African Region the present document outlines recent
revisions made by WHO to the clinical staging of HIV/AIDS and to
case definitions for HIV/AIDS disease surveillance. These interim guidelines are
based on an international drafting meeting held in Saas Fee in June 2004 and
on recommendations made by experts from African countries at a meeting held
in Nairobi in December of the same year.

The revisions to the clinical staging target professionals ranging from senior
consultants in teaching and referral hospitals to surveillance officers and first-
level health care providers, all of whom have important roles in caring for
people living with HIV and AIDS (PLWHA), including children. It is proposed that
countries review, adapt and repackage the guidelines as appropriate for specific
tasks at different levels of health service delivery. It is hoped that national HIV/
AIDS programmes in African countries will thus be assisted to develop, revise or
strengthen their ART guidelines, patient monitoring and surveillance efforts.

The interim clinical staging and revised definitions for surveillance are currently
being reviewed in the other WHO regions and will be finalized at a global
meeting to be held in September 2005.

1 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
BACKGROUND

H
IV/AIDS surveillance is useful for monitoring temporal, geographical and
risk-group trends and for estimating the burden of HIV/AIDS-related
disease. Surveillance definitions were introduced in 1982, and many
different definitions have been used for national and international reporting (1).
The clinical case definitions recommended by WHO in 1985 and revised in 1994
are designed for use in resource-limited settings. They require confirmation of
HIV infection by means of serological testing. The surveillance definitions were
introduced before the widespread use of antiretroviral therapy (ART), which
can restore many patients with severe disease to health, and reverse disease
progression. Surveillance now needs to capture those patients in need of ART.

The WHO clinical staging system for HIV/AIDS, as developed in 1990,


emphasized the use of clinical parameters to guide clinical decision-making for
the management of HIV/AIDS patients. It was designed for use in resource-
limited settings where there was limited access to laboratory services. The WHO
clinical staging system has been widely used in resource-limited countries,
particularly in the African Region, and has proved pragmatic and useful in
facilities at both the first level and the referral level. It was originally hierarchal
in recognition of the relentless progression of HIV infection, with no reversal or
improvement allowed. Unfortunately confusion has occurred with clinical case
definitions for surveillance being used for clinical purposes. The clinical disease
classification system of the Centers for Disease Control and Prevention (CDC)
in the USA which is based on immunological parameters (CD4 counts) clinical
parameters and virological parameters and requires laboratory confirmation of
many clinical events is designed for surveillance purposes, but is frequently used
for clinical management purposes.

In response to the changing landscape of HIV/AIDS, particularly in resource-


limited settings, and specifically to support scale up of anti-retroviral treatment,
revisions and harmonization of the clinical staging and case definitions for
surveillance are required. For this reason, WHO in collaboration with CDC, held
two expert consultative meetings, in June 2004 in Saas Fe, Switzerland and in
December 2004 in Nairobi, Kenya to review and revise the 1994 WHO clinical
staging system and AIDS case definitions. The revisions made were based upon
the best available evidence or, where evidence was inconclusive or unavailable,
on the balance of expert opinion. This present document describes the interim
WHO clinical staging system and case definitions as agreed during the second
meeting, held in Nairobi.

2
The revisions are also designed to reflect that with the use of ART HIV is a
chronic disease. ART changes the prognosis and can reverse the inevitable
progression through the clinical stages.

The revisions were designed to strengthen clinical staging and the AIDS case
definitions for both adults and children, and to simplify and standardize
definitions for use by a cross-section of health providers, programme managers
and surveillance officers. They were also intended to harmonize paediatric
and adult clinical staging and AIDS case definitions so as to improve patient
management, patient monitoring and surveillance efforts.

The aims of the proposed revisions were to:


◗ provide greater consistency between the adult and paediatric staging
systems;
◗ harmonize clinical case definitions and surveillance definitions;
◗ provide clinical and immunological staging for adults and children
based upon the degree of immunocompromise and prognosis, but that
facilitates follow up care;
◗ provide guidance on the care of children aged under 18 months, in
whom persisting maternal antibodies make it difficult to definitively
diagnose HIV infection if virological or P24 antigen testing is not readily
available;
◗ facilitate the use of the clinical staging system and HIV/AIDS case
definitions by non-specialist and non-paediatric health care workers at
the basic level and in peripheral health care facilities;
◗ assist with clinical decision-making, including decisions on starting,
substituting, switching and stopping ART, and with routine follow up
of patients on treatment;
◗ permit the inclusion of laboratory testing, especially CD4 count, where
available, so as to guide prognosis and assist in determining the need
for ART and other therapies;
◗ provide surveillance definitions for advanced stages of HIV infection
which reflect disease requiring ART either immediately or in the near
future.

The clinical staging is presented in two summary tables (1 and 4). Table 1 is to
be is used for those who are 15a years and above for whom there is confirmed
laboratory evidence of HIV infection. Table 4 concerns infants and children
aged under 15 years with confirmed laboratory evidence of HIV infection. An

a The cut off age of 15 years is applied as this is the usual cut off for surveillance definitions.

3 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
additional classification for presumptive diagnosis of clinical stage 4 (severe HIV
infection) in infants under 18 months is also available for use in situations where
definitive diagnosis of HIV infection is not readily available.

Clinical events are categorized as those where a presumptive clinical


diagnosis may be made (conditions that can be diagnosed clinically or with basic
laboratory tests) and those where a definitive diagnosis may be made (for
conditions requiring more complex and sophisticated laboratory investigations).
Also given are explanatory notes, proposed immunological staging categories,
implications for criteria to initiate ART and proposed harmonized definitions of
advanced HIV/AIDS for the purposes of surveillance. Clinical staging needs to
be performed at determination or confirmation of HIV infection, and on entry to
clinical care (pre-ART) to help guide ART and care related decisions. Assessment
of clinical stage at each clinical visit also provides useful information on current
clinical status, and can guide clinical decision making. National guidelines for
the clinical management of HIV/AIDS can be modified on this basis.

Annex 1 addresses issues related to the recognition and diagnosis of clinical


events in adults and adolescents, and key decisions related to clinical events
pre-ART and while on ART; Annex 2 does the same for infants and children.

4
REVISED WHO CLINICAL STAGING OF HIV/AIDS
FOR ADULTS AND ADOLESCENTS
(Interim African Region version for persons aged 15 years or more with positive HIV antibody test or
other laboratory evidence of HIV infection) b

TABLE 1. REVISED WHO CLINICAL STAGING OF HIV/AIDS FOR ADULTS AND ADOLESCENTS
Primary HIV infection
Asymptomatic
Acute retroviral syndrome

Clinical stage 1
Asymptomatic
Persistent generalized lymphadenopathy (PGL)

Clinical stage 2
Moderate unexplained weight loss (<10% of presumed or measured body weight)
Recurrent respiratory tract infections (RTIs, sinusitis, bronchitis, otitis media, pharyngitis)
Herpes zoster
Angular cheilitis
Recurrent oral ulcerations
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections of fingers

Clinical stage 3
Conditions where a presumptive diagnosis can be made on the basis of clinical
signs or simple investigations
Severe weight loss (>10% of presumed or measured body weight)
Unexplained chronic diarrhoea for longer than one month
Unexplained persistent fever (intermittent or constant for longer than one month)
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (TB) diagnosed in last two years
Severe presumed bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or
joint infection, meningitis, bacteraemia)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Conditions where confirmatory diagnostic testing is necessary
Unexplained anaemia (< 8 g/dl), and or neutropenia (<500/mm3) and or
thrombocytopenia (<50 000/ mm3) for more than one month

b All clinical events or conditions referred to are described in the Annexes. The UN defines
adolescents as persons aged 10−19 years but, in the present document, the category of
adults and adolescents comprises people aged 15 years and over for surveillance purposes.

5 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical stage 4
Conditions where a presumptive diagnosis can be made on the basis of clinical
signs or simple investigations
HIV wasting syndrome
Pneumocystis pneumonia
Recurrent severe or radiological bacterial pneumonia
Chronic herpes simplex infection (orolabial, genital or anorectal of more than one month’s
duration)
Oesophageal candidiasis
Extrapulmonary TB
Kaposi’s sarcoma
Central nervous system (CNS) toxoplasmosis
HIV encephalopathy
Conditions where confirmatory diagnostic testing is necessary:
Extrapulmonary cryptococcosis including meningitis
Disseminated non-tuberculous mycobacteria infection
Progressive multifocal leukoencephalopathy (PML)
Candida of trachea, bronchi or lungs
Cryptosporidiosis
Isosporiasis
Visceral herpes simplex infection
Cytomegalovirus (CMV) infection (retinitis or of an organ other than liver, spleen or lymph nodes)
Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis)
Recurrent non-typhoidal salmonella septicaemia
Lymphoma (cerebral or B cell non-Hodgkin)
Invasive cervical carcinoma
Visceral leishmaniasis

6
EXPLANATORY NOTES
The 2005 revised clinical staging system for adults and adolescents is designed to:
◗ be used where HIV infection is confirmed by HIV antibody or virological
testing;
◗ harmonize with newly proposed immunological criteria
◗ harmonize with revised HIV/AIDS surveillance definitions

For clinical management purposes it is designed to:


◗ be used for assessment at baseline or entry into HIV care to guide
decisions on when to start cotrimoxazole prophylaxis, start ART and
other HIV related interventions;
◗ provide simple guidance to assist clinical care providers on when to start,
substitute, switch or stop ART in HIV-infected adults and adolescents,
or to trigger referral as outlined in the WHO ART guidelines for a public
health approach(2);
◗ be used to assess current clinical status of individuals in HIV care, either
on or off ART;
◗ encourage clinical care providers to offer diagnostic testing for HIV in
adults and adolescents exhibiting the clinical events suggestive of HIV
disease;
◗ prompt urgent offer of HIV diagnostic testing for stage 3 or stage
4 events either on site, or by referral for testing to a site where
immediate assessment by HIV care providers able to initiate ART can be
performed;
◗ be used to guide clinicians in assessing the response to ART, particularly
where viral load and/or CD4 counts or percentages are not widely or
easily available (new or recurrent stage 4 events may suggest failure
of response to treatment; new or recurrent stage 2 or stage 3 events
may suggest an inadequate response to treatment, potentially because
of poor adherence; however further evidence is required in order to
determine the significance of staging events once ART has commenced.
Clinical events in the first three months after ART has begun may be
caused by immune restoration syndrome (IRS) rather than a poor
response to ART).

Note: Total lymphocyte count (TLC) is not currently recommended for


monitoring therapy.

7 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Annex 1 provides further descriptions of each clinical event and their diagnosis
clinically or with basic laboratory or radiological investigations (presumptive
diagnosis) and on requirements for more sophisticated investigations (definitive
diagnosis).

For surveillance purposes it is designed to:


◗ classify disease in a progressive sequence from least to most severe and
remains hierarchical (with only the first stage 3 or stage 4 clinical event
requiring notification);
◗ be used with reference to current clinical events, meaning those that
have been diagnosed or are currently being managed;
◗ be considered in relation to previous clinical events, such as reported
TB, severe pneumonia, PCP or other conditions; this is retrospective
clinical staging for surveillance.

IMMUNOLOGICAL STAGING OF HIV INFECTION


Clinical staging can be used effectively without access to CD4 or other
laboratory testing. However, CD4 testing is useful for determining the degree
of immunocompromise, and where CD4 facilities are available they should be
used to support and reinforce clinical decision-making. Data on CD4 levels are
not a prerequisite for starting ART and should only be used in conjunction with
consideration of the clinical stage. Table 2 presents CD4 levels in relation to the
severity of immunosuppression.

For clinical purposes long term prognosis has been shown to be related to the
nadir or lowest-ever value of CD4. It should be noted that the immunological
staging of disease reverses with successful ART.

TABLE 2. CD4 LEVELS IN RELATION TO THE SEVERITY OF IMMUNOSUPPRESSION


Not significant immunosuppression >500/mm3

Mild immunosuppression 350 − 499/mm3

Advanced immunosuppression 200 −349/mm3

Severe immunosuppression <200/mm3

8
IMPLICATIONS FOR CLINICAL AND IMMUNOLOGICAL CRITERIA FOR
INITIATING ART IN ADULTS AND ADOLESCENTS

There is strong evidence for the clinical benefit of ART in adults with advanced
HIV/AIDS as determined clinically or immunologically. The precise clinical and
or immunological criteria for initiating ART is usually outlined in national
treatment guidelines. Existing WHO recommendations are provided on a
WHO web site (2).

TABLE 3. CLINICAL AND IMMUNOLOGICAL CRITERIA FOR INITIATING ART IN ADULTS


AND ADOLESCENTS

Clinical stage ART

4 Treat.

Consider treatment: CD4, if available, can guide


3
the urgency with which ART should be started.

1 or 2 Only if CD4 <200/mm3.

CD4 can be used to monitor responses to treatment, although they are not
essential. Absolute CD4 values also fluctuate with intercurrent illness and
with physiological and test variability, so the trend over two or three repeated
measurements is usually more informative than individual values. Note: that
during the course of acute HIV infection the CD4 count may reach very low
levels and then recover.

9 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
PROPOSED HARMONIZED DEFINITIONS OF ADVANCED
HIV/AIDS DISEASE FOR SURVEILLANCE IN
ADULTS AND ADOLESCENTS

AIDS case definitions first developed in 1982 were primarily designed as an


epidemiological tool for surveillance purposes. Various revisions over the next
two decades led to inclusion of clinical and laboratory criteria to the surveillance
definitions. WHO introduced a clinical case definition for surveillance in 1985,
and revised this in 1986 and 1994 to include serological testing for HIV.

‘AIDS’ as a term has also been used to describe the various clinical syndromes,
specific opportunistic infections or malignancies that occur with HIV infection
and signal those in whom advanced HIV infection has occurred. There has been
confusion between surveillance definitions and clinical staging definitions. These
guidelines seek to harmonize both. In the present context of scaling up ART the
purpose of surveillance is to monitor the burden of advanced HIV disease and
allow estimates of the number of people who require or may shortly require
ART.

Including a CD4 threshold in surveillance definitions specifies the level at which


advanced HIV related immunosuppression is deemed to have occurred and from
which intervention with ART is immediately or soon needed to offset disease
progression. For surveillance purposes once the clinical OR immunological trigger
event has occurred the patient should be captured only once in surveillance
data, regardless of ART or other treatment interventions or outcomes.

BOX 1. ADVANCED HIV/AIDS DISEASE DEFINITIONS FOR SURVEILLANCE


Any clinical stage 3 or stage 4 disease
or,
where CD4 is availablec, any clinical stage and CD4 <350/mm3.

c CD4 based reporting remains optional

10
REVISED WHO CLINICAL STAGING OF HIV/AIDS FOR
INFANTS AND CHILDREN
(INTE RIM AFRICAN RE GION VE RSION FOR P E RSONS AGE D UND E R 15 YE ARS W ITH
CON fiRM E D LAB ORATORY E VID E NCE OF
HIV INFE CTION : HIV ANTIB OD Y IF AGE D 18 M ONTH S AND
AB OVE ; VIROLOGICAL OR P24 ANTIGE N TE STING IF AGE D UND E R 18 M ONTH S ) D

TABLE 4. REVISED WHO CLINICAL STAGING OF HIV/AIDS FOR INFANTS AND CHILDREN
Clinical Stage 1

Asymptomatic
PGL

Clinical Stage 2

Hepatosplenomegaly
Papular pruritic eruptions
Seborrhoeic dermatitis
Extensive human papilloma virus infection
Extensive molluscum contagiosum
Fungal nail infections
Recurrent oral ulcerations
Lineal gingival erythema (LGE)
Angular cheilitis
Parotid enlargement
Herpes zoster
Recurrent or chronic RTIs (otitis media, otorrhoea, sinusitis)

Clinical Stage 3

Conditions where a presumptive diagnosis can be made on the basis of clinical


signs or simple investigations
Moderate unexplained malnutrition not adequately responding to standard therapy
Unexplained persistent diarrhoea (14 days or more )
Unexplained persistent fever (intermittent or constant, for longer than one month)
Oral candidiasis (outside neonatal period )
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis/periodontitis
Pulmonary TB
Severe recurrent presumed bacterial pneumonia

d All clinical events or conditions referred to are described in the Annexes.

11 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Conditions where confirmatory diagnostic testing is necessary
Chronic HIV-associated lung disease including brochiectasis
Lymphoid interstitial pneumonitis (LIP)
Unexplained anaemia (<8g/dl), and or neutropenia (<1000/mm3) and or
thrombocytopenia (<50 000/ mm3) for more than one month

Clinical Stage 4

Conditions where a presumptive diagnosis can be made on the basis of clinical


signs or simple investigations
Unexplained severe wasting or severe malnutrition not adequately responding to standard
therapy
Pneumocystis pneumonia
Recurrent severe presumed bacterial infections (e.g. empyema, pyomyositis, bone or joint
infection, meningitis, but excluding pneumonia)
Chronic herpes simplex infection; (orolabial or cutaneous of more than one month’s duration)
Extrapulmonary TB
Kaposi’s sarcoma
Oesophageal candidiasis
CNS toxoplasmosis (outside the neonatal period)
HIV encephalopathy

Conditions where confirmatory diagnostic testing is necessary


CMV infection (CMV retinitis or infection of organs other than liver, spleen or lymph nodes;
onset at age one month or more)
Extrapulmonary cryptococcosis including meningitis
Any disseminated endemic mycosis (e.g. extrapulmonary histoplasmosis, coccidiomycosis,
penicilliosis)
Cryptosporidiosis
Isosporiasis
Disseminated non-tuberculous mycobacteria infection
Candida of trachea, bronchi or lungs
Visceral herpes simplex infection
Acquired HIV associated rectal fistula
Cerebral or B cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy (PML)
HIV-associated cardiomyopathy or HIV-associated nephropathy

12
PRESUMPTIVE DIAGNOSIS OF CLINICAL STAGE 4 HIV IN
CHILDREN AGED UNDER 18 MONTHS

The presumptive diagnosis is designed for use where access to confirmatory


diagnostic testing for HIV infection by means of virological testing (usually nucleic
acid testing, NAT) or P24 antigen testing for infants and children aged under 18
months is not readily available. It is not recommended for use by clinical care
providers who are not trained in ART or experienced in HIV care. It should
be accompanied by immediate efforts to confirm the HIV diagnosis with the best
nationally or locally available test for age. Presumptive diagnosis of clinical stage 4
disease suggests severe immunosuppression, and ART is indicated.

BOX 2. PRESUMPTIVE CLINICAL STAGE 4 IN INFANTS AND CHILDREN AGED UNDER


18 MONTHS WHERE VIROLOGICAL CONFIRMATION OF HIV INFECTION IS NOT AVAILABLE
A presumptive diagnosis of stage 4 clinical disease
should be made if:
An infant is HIV-antibody positive (ELISA or rapid test), aged under 18 months
and symptomatic with two or more of the following:
+/– oral thrush;
+/– severe pneumonia e
+/– severe wasting/malnutrition
+/– severe sepsis f
CD4 values, where available, may be used to guide decision-making; CD4
percentages below 25% require ART
Other factors that support the diagnosis of clinical stage 4 HIV infection in an
HIV-seropositive infant are:
• recent HIV related maternal death
• advanced HIV disease in the mother.
Confirmation of the diagnosis of HIV infection should be sought as soon as
possible.

EXPLANATORY NOTES
The 2005 revised clinical staging system for infants and children is designed to:
◗ be used where HIV infection is confirmed by HIV antibody or virological
testing;
◗ harmonize with newly proposed immunological criteria
◗ harmonize with revised HIV/AIDS surveillance definitions

e Pneumonia requiring oxygen.


f Requiring intravenous therapy.

13 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
For clinical management purposes it is designed to:
◗ be used for assessment at baseline or entry into HIV care to guide
decisions on when to start cotrimoxazole prophylaxis, start ART and
other HIV related interventions;
◗ provide simple guidance to assist clinical care providers on when to
start, substitute, switch or stop ART in HIV-infected children, or to
trigger referral as outlined in the WHO ART guidelines for a public
health approach(2);
◗ be used to assess current clinical status of children in HIV care, either on
or off ART;
◗ encourage clinical care providers to offer HIV diagnostic testing in infants
and children exhibiting clinical events suggestive of HIV disease;
◗ prompt urgent referral for diagnostic HIV testing and assessment for all
Stage 3 or stage 4 events in children where HIV status is unknown or a
child is known to be HIV exposed;
◗ be used to guide clinicians in assessing the response to ART, particularly
where viral load and/or CD4 counts or percentages are not widely
or easily available (however, further evidence is required in order to
determine the significance of staging events once ART has been started;
new or recurrent stage 4 events may suggest a failure of response to
treatment; new or recurrent stage 2 or stage 3 events may suggest
an inadequate response to treatment, potentially attributable to poor
adherence); note that clinical events in the first three months after
starting ART may be attributable to IRS rather than a poor response to
ART; this is reported less commonly in children;

Note: Total lymphocyte count (TLC) is not currently recommended for


monitoring therapy.

Annex 2 provides further descriptions of each clinical event and their diagnosis
clinically or with basic laboratory or radiological investigations (presumptive
diagnosis) and on requirements for more sophisticated investigations (definitive
diagnosis).

For surveillance purposes it is designed to;


◗ classify disease in a progressive sequence from least to most severe and
remains hierarchical (with only the first stage 3 or stage 4 clinical event
requiring notification);
◗ be used with reference to current clinical events, meaning those that
have been diagnosed or are currently being managed;

14
◗ be considered in relation to previous clinical events, such as reported
TB, severe pneumonia, PCP or other conditions; this is retrospective
clinical staging for surveillance.

IMMUNOLOGICAL CATEGORIES FOR PAEDIATRIC


HIV INFECTION
Immunological staging for children is also possible. The absolute CD4 count
and the percentage values in healthy infants who are not infected with HIV
are considerably higher than those observed in uninfected adults, and slowly
decline to adult values by the age of 6 years. In considering absolute counts
or percentages, therefore, age must be taken into account as a variable. The
absolute CD4 count associated with a specific level of immunosuppression tend
to change with age, whereas the CD4 percentage related to immunological
damage does not vary as much. Currently, therefore, the measurement of
the CD4 percentage is recommended in younger children. CD4 testing is not
essential for the initiation of ART, and should only be used in conjunction with
the clinical stage. As for adults, immunological staging assists clinical decision-
making and provides a link with monitoring and surveillance definitions. It is
usually reversed by successful ART.

TABLE 5. CD4 LEVELS IN RELATION TO THE SEVERITY OF IMMUNOSUPPRESSION

Age

Up to 12 13-59 5 years or
Immune status months months over

Not significant immunosuppression >35% >25% >500/mm3

Mild immunosuppression 25−34% 20−24% 350−499/mm3

Advanced immunosuppression 20−24% 15−19% 200−349/mm3

Severe immunosuppression <20% <15% <200/mm3

15 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
IMPLICATIONS FOR CLINICAL AND IMMUNOLOGICAL
CRITERIA FOR INITIATING ART

Although there are concerns about the early use of ART in asymptomatic infants,
all children with stage 3 or stage 4 disease (advanced HIV defined clinically)
should start ART following discussion with their families. There is very strong
evidence for the clinical benefit of ART in children with advanced HIV/AIDS. For
older children some clinical conditions, e.g. LIP, appear to have a more stable
clinical course, although there are few data on cohorts from African settings.
Because of the revisions in clinical staging these recommendations should
replace those provided in the 2003 WHO reference guide (2).

TABLE 6. CLINICAL AND IMMUNOLOGICAL CRITERIA FOR INITIATING ART IN


INFANTS AND CHILDREN

Clinical stages ART

4 Treat.

Presumptive stage 4 Treat.

Consider treatment for all ages. Children aged


under 2 years usually require ART.
3
CD4 %, if available should be used to guide
decisions on ART.

Usually only where CD4 available.

1 and 2 Under 12 months: CD4 % < 20


13-59 months : CD4 % < 15
5 years or over CD4 <200/mm3

Note: co-trimoxazole prophylaxis should be given to all HIV-exposed infants


and children until HIV infection is excluded and to all HIV-infected infants and
children

CD4 can be used to monitor responses to treatment, although it is not essential.


Absolute CD4 values also fluctuate with intercurrent illness and with physiological
and test variability, so the trend over two or three repeated measurements is
usually more informative than individual values.

16
PROPOSED HARMONIZED DEFINITIONS OF ADVANCED
HIV/AIDS DISEASE FOR SURVEILLANCE IN
CHILDREN AGED UNDER 15 YEARS

The surveillance of paediatric HIV/AIDS can provide estimates of the number


of infants and children who require or may shortly require ART. AIDS case
definitions for surveillance have until recently only been provided by CDC and
include laboratory criteria. There has been confusion between surveillance
definitions and clinical staging definitions.

These guidelines propose age-related clinical and immunological case definitions


of advanced HIV/AIDS disease in infants and children for surveillance purposes.
Age-related definitions are required because of the age-related changes in
immunological markers. Advanced HIV disease for surveillance purposes should
be reported only once for each individual.

BOX 3. ADVANCED HIV/AIDS DISEASE DEFINITIONS FOR SURVEILLANCE FOR


INFANTS AND CHILDREN

Clinical stage 3 or stage 4 disease at any age


or
where CD4 is availableg, any clinical stage with
• CD4 % <25% in children aged under 12 months
• CD4 % <20% in children aged 12 -59 months
• CD4 <350/mm3 in children aged 5 years and above

g CD4 based reporting remains optional

17 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
RECOMMENDATIONS FOR IMPLEMENTATION
The following recommendations concern the use of the revised clinical staging
and HIV/AIDS case definitions for clinical management and case-reporting.
◗ The revised clinical staging should be used to update and strengthen
national guidelines so as to ensure that they provide clear guidance on
which clinical and immunological stages require or are eligible for co-
trimoxazole prophylaxis and ART treatment and support patient follow up.
◗ All infants, children, adolescents and adults with clinical stage 3 or stage
4 disease should be reported as having advanced HIV/AIDS disease. Such
case reports can be used to calculate the burden of HIV/AIDS which
immediately requires or will soon require ART. HIV/AIDS reporting for
surveillance should preserve patient confidentiality in accordance with
existing national or international recommendations.
◗ National HIV/AIDS programmes should be encouraged to support
CD4-based HIV/AIDS case-reporting for surveillance.

The following additional recommendations concern actions facilitating the


use of the interim clinical staging system and HIV/AIDS case definitions for
surveillance.

Actions at the global and regional level:


◗ At the global level, WHO should publish details of the new HIV/AIDS
clinical staging.
◗ At the global level, WHO should develop and disseminate guidelines
on the use of the revised HIV clinical staging system and of the revised
case definitions.
◗ At the regional level, WHO should organize intercountry meetings in
order to introduce the revisions and to encourage rapid implementation
in countries.
◗ WHO and CDC should incorporate the proposed revisions to
surveillance definitions into surveillance training materials that are
under development.
◗ WHO and CDC should provide technical support for the adoption and
scaling-up for implementation of these revisions in countries.
◗ WHO and CDC should provide technical support for the development
of systems for reporting AIDS-related deaths.
◗ WHO and CDC will hold a meeting during the fourth quarter of 2006
in order to review and update the clinical staging system and case
definitions.

18
Actions at the national level
◗ Ministries of health and their partners should organize national
consensus meetings on the proposed revisions, and should adapt and
repackage the regional guidelines in accordance with existing national
specifications in a way that is appropriate for use at different levels of
health service delivery.
◗ Ministries of health should integrate the proposed revisions into
existing guidelines and procedures for HIV/AIDS clinical management
and HIV/AIDS case-reporting.
◗ Ministries of health should organize in-country training in order to build
capacity for the implementation of the revisions, including integration
into the curricula of relevant professional and non-professional training
institutions.
◗ Ministries of health should produce simplified wall charts, laminated
desk-top guides, pocket guides and other materials facilitating the use
of the recommended revisions.
◗ Ministries of health should establish systems for HIV/AIDS reporting in
children at a few sentinel sites where children are seen to improve and
strengthen the provision of information on children with HIV/AIDS.
◗ Ministries of health should ensure that reliable systems are in place for
reporting AIDS-related deaths.

19 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
ANNEX 1.
WHO CLINICAL STAGING FOR ADULTS AND ADOLESCENTS:
PRESUMPTIVE AND DEFINITIVE CRITERIA FOR RECOGNIZING
HIV/AIDS-RELATED CLINICAL EVENTS
(For use in adults and adolescents aged 15 years and above with laboratory evidence of HIV infection.)

Clinical event Presumptive diagnosis Definitive diagnosis

Primary HIV infection

Asymptomatic Detectable core P24


antigen and high blood HIV
Acute retroviral syndrome Acute febrile illness 2−4 weeks
RNA, profound temporary
post-exposure, often with
lymphopenia and other
lymphadenopathy, pharyngitis
transient blood abnormalities
and skin manifestations.
may occur. Not usually HIV
antibody-positive until after
symptoms.
Seroconversion from HIV Ab-
negative to Ab-positive.

Clinical Stage 1

Asymptomatic No symptoms reported and no Not required.


signs on examination.

Persistent generalized Swollen or enlarged lymph Not required but can be


lymphadenopathy nodes >1 cm, in two or more confirmed by histology
(PGL) non-contiguous sites, excluding (germinal centre hyperplasia,
inguinal nodes, in absence of lymph node structure
known cause. preserved).

Clinical Stage 2

Moderate unexplained weight Reported weight loss but no Confirmed by documented


loss (<10% of presumed or obvious thinning of face or weight loss.
measured body weight) body.

Recurrent presumed bacterial Symptom complex, e.g. Not required but may be
RTI unilateral face pain with confirmed by laboratory studies
(two or more in any six-month nasal discharge (sinusitis) or where available, e.g. culture of
period) painful swollen eardrum (otitis suitable body fluid.
media), cough with purulent
sputum (bronchitis), sore throat
(pharyngitis). Two or more
documented occurrences of
antibiotic- responsive URTI.

20
Clinical event Presumptive diagnosis Definitive diagnosis

Herpes zoster Painful rash of small fluid- Not required.


filled blisters in distribution
of a nerve supply, can be
haemorrhagic on erythematous
background, and does not
cross midline. Current or in
the last two years. Severe or
frequently recurrent herpes
zoster is usually associated
with more advanced HIV
disease.

Angular cheilitis Splits or cracks on lips at Not required.


the angle of the mouth with
depigmentation, usually
responds to antifungal
treatment but may recur.
Also common in nutritional
deficiency, e.g. of B vitamins.

Recurrent oral ulcerations Aphthous ulceration, Not required.


occurring twice or more in six typically with a halo of
months inflammation and a yellow-grey
pseudomembrane.

Papular pruritic eruptions Papular pruritic vesicular Not required.


lesions. Also common in
uninfected adults.
Note: scabies and obvious
insect bites should be excluded.

Seborrhoeic dermatitis Itchy scaly skin condition, Not required.


particularly affecting scalp,
face, upper trunk and
perineum. Also common in
uninfected adults.

Fungal nail infections of fingers Fungal paronychia (painful Not required but confirmed by
red and swollen nail bed) or culture of nail scrapings.
onycholysis (separation of the
nail from the nail bed) of the
fingernails. Also common in
uninfected adults. Proximal
white subungual onchomycosis
is uncommon without
immunodeficiency.

21 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical Stage 3

Clinical event Presumptive diagnosis Definitive diagnosis

Severe unexplained weight loss Reported weight loss without Documented loss of more than
(more than 10% of presumed trying, and noticeable thinning 10% of body weight.
or measured body weight) of face, waist and extremities.

Unexplained chronic diarrhoea Chronic diarrhoea (loose or Not required but confirmed if
for longer than one month watery stools three or more three or more stools observed
times daily) reported for longer and documented as unformed,
than one month. and two or more stool tests
reveal no pathogens on
microscopy and culture and no
faecal leukocytes.

Unexplained persistent fever Reports of fever or night Not required but confirmed if
(intermittent or constant and sweats for more than one documented fever >37.5 °C
for longer than one month) month, either intermittent or with negative blood culture,
constant with reported lack negative Ziehl-Nielsen (ZN)
of response to antibiotics or stain, negative malaria slide,
antimalarials. No other obvious normal or unchanged chest X-
foci of disease reported or ray (CXR) and no other obvious
found on examination. Malaria foci of disease.
must be excluded in malarious
areas.

Oral candidiasis Persistant creamy white Not required.


to yellow soft small
plaques on red or normally
coloured mucosa which
can often be scraped off
(pseudomembranous), or red
patches on tongue, palate or
lining of mouth, usually painful
or tender (erythematous
form), not responding to local
antifungal treatment.

Oral hairy leukoplakia Fine small linear patches on Not required.


lateral borders of the tongue,
generally bilaterally, which do
not scrape off.

22
Clinical event Presumptive diagnosis Definitive diagnosis

Pulmonary TB Chronic (symptoms lasting Not required but confirmed by


(current or in last two years) three or more weeks) positive sputum culture.
productive cough, haemoptysis,
shortness of breath, weight
loss, fever, night sweats
and fatigue, no resolution
of symptoms with standard
broad-spectrum antibiotics,
positive ZN stain.
Response to standard anti-TB
treatment in one month.
Note: TB diagnosis and
treatment should follow
national or international
guidelines.
CD4 should be used where
possible to guide therapy; very
low CD4 may require urgent
ART.

Severe presumed bacterial Fever accompanied by specific Not required but confirmed
infection (e.g. pneumonia, symptoms or signs that localize by bacteria isolated from
meningitis, empyema, infection, and response to appropriate clinical specimens.
pyomyositis, bone or joint antibiotic.
infection, bacteraemia )

Acute necrotizing ulcerative Severe pain, ulcerated gingival Not required.


gingivitis or necrotizing papillae, loosening of teeth,
ulcerative periodontitis spontaneous bleeding, bad
odour, and rapid loss of bone
and/or soft tissue.

Unexplained anaemia (<8g/dl), No presumptive clinical Diagnosed on laboratory


neutropenia (<1000/mm3 ) or diagnosis. testing and not explained by
thrombocytopenia(<50000/mm3) other non-HIV conditions. Not
for more than one month responding to standard therapy
with haematinics, antimalarials
or anthelmintics as outlined
in relevant national treatment
guidelines, WHO guidelines or
other relevant guidelines.

Clinical Stage 4

23 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Presumptive diagnosis Definitive diagnosis

HIV wasting syndrome Unexplained weight loss Confirmed by documented


greater than 10% of body weight loss without trying;
weight and visible thinning of plus
face, waist and extremities;
documented unformed stools
plus negative for pathogens;
either unexplained chronic negative for modified ZN;
diarrhoea (lasting more than or
one month)
Documented temperature of
or 37.5 °C or more on occasions
unexplained prolonged or with no obvious foci of disease,
intermittent fever for one negative blood culture, negative
month or more. malaria slide and normal or
unchanged CXR.

Pneumocystis pneumonia Dry cough, progressive Not required but confirmed by:
shortness of breath, especially microscopy of induced sputum
on exertion, with cyanosis, or bronchoalveolar lavage
tachypnoea and fever, (BAL), or histology of lung
response to high-dose co- tissue.
trimoxazole +/– prednisolone.
Bilateral crepitations on
auscultation with or without
reduced air entry.
CXR may show typical bilateral
interstitial infiltrate with bat
wing appearance.

Recurrent severe or radiological Two episodes of fever, wet Not required but confirmed
bacterial pneumonia (two or cough, fast and difficult by culture or antigen test from
more episodes within one year) breathing and chest pain. appropriate specimen.
Consolidation on clinical
examination and CXR.
Response to antibiotics.

Chronic herpes simplex virus Severe and progressive painful Not required for mucocutanoues
(HSV) infection (orolabial, orolabial, genital, or anorectal HSV but required for visceral
genital or anorectal of more lesions caused by recurrent HSV. Suggestive symptoms of
than one month, or visceral of HSV infection reported for organ damage, e.g. bronchitis,
any duration) more than one month. History pneumonitis, oesophagitis,
of previous episodes. Scarring colitis, encephalitis, supported
from previous episodes may be by histology or culture.
evident.

24
Clinical event Presumptive diagnosis Definitive diagnosis

Oesophageal candidiasis Chest pain and dysphagia Not required but confirmed by
(difficulty in swallowing), macroscopic appearance at
odynophagia (pain on endoscopy or bronchoscopy,
swallowing food and fluids), microscopy or histology.
or retrosternal pain worse on
swallowing (food and fluids)
+/– oral Candida. Responds
to antifungal treatment.

Extrapulmonary/disseminated Systemic illness usually with Not required but confirmed by


TB prolonged fever, night sweats, acid-fast bacilli (AFBs) seen in
weakness and weight loss. microscopy of cerebrospinal
Clinical features of organs fluid (CSF), effusion, lymph
involved, e.g. focal node aspirate, urine, etc.
lymphadenopathy, cold Mycobacteria TB isolated from
abscess, sterile pyuria, blood culture or any appropriate
pericarditis, ascites, pleural specimen except sputum or
effusion, meningitis, arthritis, BAL.
orchitis, lupus vulgaris. Histology (e.g. pleural or
CXR may reveal diffuse pericardial biopsy).
uniformly distributed small CXR may show interstitial
miliary shadows infiltrates.
Response to standard anti-TB Lymphocytic CSF with
treatment in one month. typical abnormalities, no
bacterial growth and negative
cryptococcal antigen (CRAG).

Kaposi’s sarcoma Typical appearance in skin Not required but may be


or oropharynx of persistent, confirmed by :
initially flat, patches with a • typical red-purple lesions
pink or blood-bruise colour, seen on bronchoscopy or
skin lesions that usually endoscopy;
develop into nodules. Can
be confused clinically with • dense masses in lymph nodes,
bacillary angiomatosis, non- viscera or lungs by palpation
Hodgkin lymphoma and or radiology;
cutaneous fungal or bacterial • histology.
infections.

25 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Presumptive diagnosis Definitive diagnosis

CMV (retinitis or CMV infection Retinitis only. Definitive diagnosis required for
of an organ other than liver, CMV retinitis may be diagnosed other sites. Symptoms and signs
spleen or lymph nodes) by experienced clinicians. of other organ involvement,
Progressive floaters in field e.g. pneumonitis, pancreatitis,
of vision, light flashes and colitis, cholecystitis, not
scotoma. responding to co-trimoxazole
or antibiotics. Histology. CSF
Typical eye lesions on serial polymerase chain reaction
fundoscopic examination; (PCR).
discrete patches of retinal
whitening with distinct borders,
spreading centrifugally, often
following blood vessels,
associated with retinal
vasculitis, haemorrhage and
necrosis.

CNS toxoplasmosis Fever, headache, focal Not required but confirmed by


neurological signs, convulsions. computed tomography (CT)
Rapid response (within 10 scan showing single/multiple
days) to high-dose lesions with mass effect/
co-trimoxazole, or enhancing with contrast.
pyrimethamine and If lumbar puncture (LP)
sulphadiazine or clindamycin. performed, CSF nonspecific or
normal. Resolution of findings
after treatment if patient
survives.

Cryptococcal meningitis Meningitis: usually subacute, Confirmed by CSF microscopy


or other extrapulmonary fever with increasing severe (India ink or Gram stain).
Cryptococcus infection headache, meningism, Serum or CSF CRAG-positive or
confusion, behavioural changes. culture-positive.
Responds to antifungal
therapy.

HIV encephalopathy Clinical finding of disabling Recommended to confirm


cognitive and/or motor clinical features and exclude
dysfunction interfering with other causes including
activities of daily living, neurosyphilis:
progressing over weeks or • brain scan by means of
months in the absence of a CT or magnetic resonance
concurrent illness or condition imaging (MRI) with
other than HIV infection which
might explain the findings. • LP.

LP should be conducted to
exclude other infectious causes.

26
Clinical event Presumptive diagnosis Definitive diagnosis

Disseminated non-tuberculous No presumptive diagnosis. Nonspecific clinical symptoms


mycobacteria infection including progressive weight
loss, fever, anaemia, night
sweats, fatigue or diarrhoea.
Severe anaemia and/or elevated
alkaline phosphatase and/or
(in case of diarrhoea) persisting
AFB in the stool in spite of TB
therapy.
Plus:
Culture of atypical mycobacteria
species from stool, blood,
body fluid or other body tissue,
excluding lung.

PML No presumptive diagnosis. Progressive focal neurological


signs without headache or
fever, cortical blindness,
cerebellar signs, dementia.
Confirmed by consistent MRI
or CT scan, and biopsy. Viral
PCR for Jacob Creutzfeldt virus.

Candidiasis of trachea, bronchi, No presumptive diagnosis. Confirmed by symptoms,


lungs clinical signs suggestive of
organ involvement and/or
macroscopic appearance at
bronchoscopy. Histology or
cytology, or microscopy of
specimen from tissue.

Cryptosporidiosis (with No presumptive diagnosis. Chronic diarrhoea, often profuse


diarrhoea lasting more than one and watery, with weight loss,
month) ± abdominal pain, nausea,
vomiting; confirmed by modified
ZN microscopic examination
of stool. Stools observed to
be unformed with organism
visualized in stool sample.

Isosporiasis No presumptive diagnosis. Watery diarrhoea, cramps and


weight loss. Symptoms usually
indistinguishable from those of
cryptosporidiosis.
Isosporiaisis responds to high-
dose cotrimoxazole.

27 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Presumptive diagnosis Definitive diagnosis

Any disseminated mycosis (e.g. No presumptive diagnosis. Clinical symptoms nonspecific,


coccidiomycosis, histoplasmosis, e.g. skin rash, cough, shortness
penicilliosis) of breath, fever, anaemia,
weight loss.
CXR: infiltrates or nodules.
Confirmed by direct microscopy.
Histology: usually granuloma
formation. Isolation: antigen
detection from affected
tissue. Skin lesion culture or
microscopy positive.

Recurrent non-typhoidal No presumptive diagnosis. Nonspecific symptoms: fever,


salmonella septicaemia (two or sweats, headaches, weight
more episodes in last year ) loss, diarrhoea and anorexia.
Confirmed by blood culture.

Lymphoma (cerebral or B cell No presumptive diagnosis. Symptoms consistent with


non-Hodgkin) lymphoma: lymphadenopathy,
splenomegaly, pancytopenia,
testicular or lung mass lesions;
no response clinically to
antitoxoplasma or anti-TB
treatment.
CNS imaging: at least one
lesion with mass effect on brain
scan; histology.

Invasive cervical carcinoma No presumptive diagnosis. Persistent vaginal discharge,


postcoital or intermenstrual
bleeding unresponsive to
appropriate antibacterial or
antifungal treatment; cervical
lesions visualized. Histology.
Cytology, but not carcinoma
in situ.

Visceral leishmaniasis No presumptive diagnosis. Suggestive symptoms:


malaise, chronic fever,
hepatosplenomegaly,
pancytopenia . Amastigotes
visualized or cultured from any
appropriate clinical specimen.

28
CLINICAL STAGING EVENTS AS A TOOL TO GUIDE
CLINICAL MANAGEMENT IN ADULTS AND ADOLESCENTS
( PRE-ART AND ART FOLLOW-UP CARE)

The same criteria for presumptive and definitive diagnosis apply

Clinical events pre-ART Action

Stage 1 No action required

Stage 2 Requires cotrimoxazole

Stage 3 Requires cotrimoxazole if not already started


Or Consider ART
Stage 4 First ever occurrence of a stage 3 or 4 event requires notification
for surveillance purposes

Clinical events on ART Action

Stage 1 Consider interruption of cotrimoxazole if stable on ART for


6 months or more.

New or recurrent : Check adherence


Stage 2 Treat and manage condition
or Restart cotrimoxazole
stage 3 Should alert the provider to the possibility of poor adherence or
failing response to treatment.

New or recurrent Check adherence


Stage 4 Treat and manage condition
Restart cotrimoxazole
Consider regimen switch
Suggest failure to respond to ART, possibly because of true failure
of the regimen and/or poor adherence.

29 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
ANNEX 2.
WHO CLINICAL STAGING FOR INFANTS AND CHILDREN :
PRESUMPTIVE AND DEFINITIVE CRITERIA FOR RECOGNIZING
HIV/AIDS-RELATED CLINICAL EVENTS
(For use in infants and children aged under 15 years with laboratory evidence of HIV infection: HIV
antibody in those aged 18 months and above, DNA or RNA virological testing or P24 antigen testing
for those aged under 18 months.)

Highlighted events are still awaiting further data for clarification of definitions

Clinical event Clinical diagnosis Definitive diagnosis

Clinical Stage 1

Asymptomatic No symptoms reported and no Not required.


signs on examination.

PGL Swollen or enlarged lymph Not required.


nodes >1 cm at two or more (Histology; germinal centre
non-contiguous sites, without hyperplasia, lymph node
known cause. structure preserved.)

Clinical Stage 2

Hepatosplenomegaly Unexplained enlarged liver or Not required.


spleen.

Papular pruritic eruptions Persistent papular pruritic Not required.


vesicular lesions; scabies
should be excluded.

Seborrhoeic dermatitis Itchy scaly skin condition Not required.


particularly affecting scalp, face,
upper trunk and perineum. Also
common in uninfected children
and in babies.

Fungal nail infections Fungal paronychia (painful, Culture of nail scrape.


red and swollen nail bed)
or onycholysis (painless
separation of the nail from
the nail bed). Proximal white
subungual onchomycosis
is uncommon without
immunodeficiency.

30
Clinical event Clinical diagnosis Definitive diagnosis

Angular cheilitis Splits or cracks on lips at Not required.


the angle of the mouth with
depigmentation, usually
responding to antifungal
treatment but may recur.
Also common in nutritional
deficiency, e.g. of B vitamins.

LGE Erythematous band that Not required.


follows the contour of the
free gingival line; may be
associated with spontaneous
bleeding.
Uncommon in HIV-uninfected
children.

Human papilloma virus infection Characteristic skin lesions; Not required.


(extensive facial, more than 5% warts; small fleshy grainy
of body area or disfiguring) bumps, often rough, on sole of
feet are flat (plantar warts).
Also common in uninfected
children.

Molluscum contagiosum Characteristic skin lesions: Not required.


infection small flesh-coloured, pearly
(extensive facial, more than 5% or pink, dome-shaped or
of body area or disfiguring) umbilicated growths, may be
inflamed or red.
Also common in uninfected
children.

Recurrent oral ulcerations Aphthous ulceration, Not required.


(two or more in six months) typically with a halo of
inflammation and a yellow-grey
pseudomembrane.

Parotid enlargement Asymptomatic bilateral swelling Not required.


that may spontaneously resolve
and recur, in absence of other
known cause, usually painless.
Uncommon in HIV-uninfected
children.

31 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Clinical diagnosis Definitive diagnosis

Herpes zoster Painful rash with fluid- Viral culture, histology, EM of


filled blisters, dermatomal lesion fluid.
distribution, can be
haemorrhagic on erythematous
background, and can become
large and confluent. Does not
cross the midlines. Note: severe
persistent herpes zoster may
have worse prognosis.

Recurrent RTI Symptom complex, e.g. fever Not required but may be
(twice or more in any six-month with unilateral face pain and confirmed by laboratory or
period) nasal discharge (sinusitis) X-ray studies where available,
or painful swollen eardrum especially for sinus, and culture
(otitis media), sore throat with or appropriate specimens.
productive cough ( bronchitis),
sore throat (pharyngitis) and
barking croup-like cough (LTB).
Persistent or recurrent ear
discharge.

Clinical Stage 3

Unexplained moderate Unexplained weight loss Documented loss of body


malnutrition (very low weight- or failure to gain weight weight, failure to gain weight
for-age: up to −2 standard not explained by poor or on standard management and
deviations (SDs) (3, 4) ; not inadequate feeding or other no other cause identified during
responding adequately to infections , and not adequately investigation.
standard therapy, responding within two weeks
to standard management ,

Unexplained persistent Unexplained persistent Not required, but confirmed


diarrhoea diarrhoea (loose or watery if stools observed and
(14 days and above) stool, three or more times documented as unformed.
daily), not responding to Culture and microscopy reveal
standard treatment. no pathogens.

Unexplained persistent fever Reports of fever or night Not required but confirmed if
(intermittent or constant and sweats for longer than one documented fever of >37.5 °C
for longer than one month) month, either intermittent or with negative blood culture,
constant, with reported lack negative malaria slide and
of response to antibiotics or normal or unchanged CXR,
antimalarials. and no other obvious foci of
No other obvious foci of disease.
disease reported or found on
examination. Malaria must be
excluded in malarious areas.

32
Clinical event Clinical diagnosis Definitive diagnosis

Oral candidiasis Persistent creamy white to Microscopy or culture.


(outside first 6 weeks of live) yellow soft small plaques
on red or normally coloured
mucosa, easily scraped off
(pseudomembranous), or red
patches on tongue, palate
or lining of mouth, usually
painful or tender, responding to
antifungal treatment.

Oral hairy leukoplakia Fine small linear patches on Not required.


lateral borders of tongue,
generally bilaterally, which do
not scrape off.

Pulmonary TB Nonspecific symptoms, Abnormal CXR plus positive


e.g. chronic cough, fever, sputum smear, or culture.
night sweats, anorexia and
weight loss. In the older child
also productive cough and
haemoptysis. Response to
standard anti-TB treatment in
one month.
Note: diagnosis should be
made in accordance with
national guidelines.

Severe recurrent presumed Cough with fast breathing, Not required but confirmed by
bacterial pneumonia chest indrawing, nasal flaring, isolation of bacteria from
wheezing, and grunting. appropriate
Crackles or consolidation on
auscultation. Responds to clinical specimens.
course of antibiotics.

Acute necrotizing ulcerative Severe pain, ulcerated gingival Not required.


gingivitis or stomatitis, or papillae, loosening of teeth,
acute necrotizing ulcerative spontaneous bleeding, bad
periodontitis odour, and rapid loss of bone
and/or soft tissue.

33 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Clinical diagnosis Definitive diagnosis

Symptomatic LIP No presumptive clinical CXR: bilateral reticulonodular


diagnosis. interstitial pulmonary infiltrates
present for more than two
months with no response
to antibiotic treatment and
no other pathogen found.
Oxygen saturation persistently
<90%. May present with
cor pulmonale and may have
increased exercise-induced
fatigue.
Frequently confused with
miliary TB.

Chronic HIV-associated No presumptive clinical History of cough productive of


lung disease (including diagnosis. copious amounts of purulent
brochiectasis) sputum, with or without
clubbing, halitosis, and
crepitations and/or wheezes
on auscultation; CXR may
show honeycomb appearance
(small cysts) and/or persistent
areas of opacification and/or
widespread lung destruction,
with fibrosis and loss of
volume. CT scan of chest may
be used to confirm.

Unexplained anaemia (< 8g/dl), No presumptive clinical Diagnosed on laboratory


and or neutropenia (<500/ diagnosis. testing, not explained by other
mm3) and or thrombocytopenia non-HIV conditions, or not
(<50 000/ mm3) for longer responding to standard therapy
than one month with haematinics, antimalarials
or anthelmintics as outlined in
IMCI.

34
Clinical Stage 4

Clinical event Clinical diagnosis Definitive diagnosis

Unexplained severe wasting Persistent weight loss not Documented loss of weight or
or severe malnutrition not explained by poor or inadequate failure to gain weight.
adequately responding to feeding, other infections and
standard therapy not adequately responding in
two weeks to standard therapy.
Characterized by:
visible severe wasting of
muscles, with or without
oedema of both feet, and/or
weight-for-height of –3 SDs, as
defined by WHO IMCI guidelines.

Pneumocystis pneumonia (PCP) Dry cough, progressive Microscopy of induced sputum


shortness of breath, cyanosis, or BAL, or histology of lung
tachypnoea and fever; chest tissue.
indrawing or stridor. Response CXR shows typical bilateral
to high-dose co-trimoxazole perihilar diffuse infiltrates.
+/– prednisolone.
(Severe or very severe
pneumonia as in IMCI). Usually
of sudden onset and very
severe in infants under six
months of age .

Recurrent severe presumed Fever accompanied by specific Not required but confirmed
bacterial infection (two or symptoms or signs that by bacteria isolated from
more episodes in one year), localize infection. Responds to appropriate clinical specimens
e.g. meningitis, empyema, antibiotics. and includes recurrent
pyomyositis, bone or joint non-typhoidal salmonella
infection, bacteraemia septicaemia.

Chronic herpes simplex virus Severe and progressive painful Visceral HSV requires
infection (chronic orolabial or orolabial or skin lesions confirmation. Suggestive
intraoral lesions of more than attributable to recurrent HSV symptoms of organ damage,
one month or visceral of any reported for more than one e.g. bronchitis, pneumonitis,
duration) month. History of previous oesophagitis, colitis,
episodes. Scarring from encephalitis, supported by
previous episodes may be histology or culture.
evident.

35 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Clinical diagnosis Definitive diagnosis

Oesophageal candidiasis Chest pain and dysphagia Not required but confirmed
(difficulty in swallowing), by macroscopic appearance
odynophagia (pain on at endoscopy, microscopy
swallowing food and fluids), of specimen from tissue or
or retrosternal pain worse on macroscopic appearance at
swallowing (food and fluids) bronchoscopy or histology.
+/– oral Candida. Responds
to antifungal treatment.
May be difficult to detect in
young children. Suspect if oral
Candida observed and if refusal
occurs or if there are difficulties
or crying when feeding.

Extrapulmonary TB TB not limited to lungs. Mycobacterium TB isolated


Systemic illness usually with form blood culture or other
prolonged fever, night sweats, specimen except sputum
weight loss. or BAL. Positive AFB on
microscopy or culture on
Clinical features of organs relevant specimens.
involved, e.g. focal
lymphadenopathy, cold Biopsy and histology. X-ray.
abscess, sterile pyuria,
pericarditis, ascites, pleural
effusion, meningitis, arthritis,
orchitis, lupus vulgaris.
Responds to standard anti-TB
therapy.
Note: simple lymph gland
extrapulmonary TB may have a
better prognosis.

Kaposi’s sarcoma Typical appearance in skin or Typical red-purple lesions seen


oropharynx, initially flat patches on bronchoscopy or endoscopy.
with a pink or blood-bruise Biopsy.
colour, usually developing into
nodules.

36
Clinical event Clinical diagnosis Definitive diagnosis

CMV retinitis and CMV No presumptive clinical Symptoms and signs of organ
infection of organs other than diagnosis. involvement, e.g. typical eye
liver, spleen or lymph nodes, Clinically, disease suspected if lesions on fundoscopy or
with onset at age over 1 month there are typical eye lesions on pneumonitis not responding to
serial fundoscopic examination; co-trimoxazole or antibiotics.
discrete patches of retinal Histology or detection of
whitening with distinct borders, antigen from affected tissue.
spreading centrifugally, often
following blood vessels,
associated with retinal vasculitis,
haemorrhage and necrosis.

CNS toxoplasmosis Fever, headache, focal CT scan showing single/


(outside the neonatal period ) neurological signs, convulsions. multiple lesions with mass
Response to high-dose co- effect/enhancing with
trimoxazole or pyrimethamine contrast. CSF results normal or
and sulphadiazine or nonspecific.
clindamycin. Resolution of findings after
treatment if patient survives.

Cryptococcal meningitis Meningitis: usually subacute, CSF: microscopy (India ink or


fever with increasing severe Gram stain)
headache, irritability, Positive serum CRAG test.
meningism, confusion,
behavioural changes. Responds
to antifungal therapy

HIV encephalopathy At least one of the following, Brain CT scan or MRI to exclude
progressing over at least two other causes.
months in the absence of
another illness:
• gross discrepancy between
the actual and developmental
age, failure to attain, or loss
of, developmental milestones,
loss of intellectual ability;
or
• progressive impaired brain
growth demonstrated
by stagnation of head
circumference;
or
• acquired symmetric motor
deficit accompanied by two
or more of the following:
paresis, pathological reflexes,
ataxia, gait disturbances.

37 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Clinical diagnosis Definitive diagnosis

Any disseminated mycosis No presumptive clinical Organ-specific and nonspecific


(e.g. histoplasmosis, diagnosis. symptoms, e.g. may cause skin
coccidiomycosis, penicilliosis) rash, or cough, shortness of
breath, fever, anaemia, weight
loss.
Diagnosis confirmed by direct
microscopy, histology or antigen
detection in relevant specimens.
CXR may show infiltrates or
nodules.

Candidiasis of the trachea, No presumptive clinical Macroscopic appearance at


bronchi or lungs diagnosis. endoscopy.
Microscopy and culture of
specimen from endoscopic
tissue.

Disseminated mycobacteriosis, No presumptive clinical Nonspecific clinical symptoms


other than TB diagnosis. including progressive weight
loss, fever, anaemia, night
sweats, fatigue or diarrhoea;
plus
culture of atypical mycobacteria
species from stool, blood,
body fluid or other body tissue,
excluding lung.

Cryptosporidiosis No presumptive clinical Chronic diarrhoea, often


(with diarrhoea lasting more diagnosis. profuse and watery, with
than one month) weight loss, ± abdominal pain,
nausea, vomiting, but usually
mild or no fever. Confirmed by
microscopic examination on
modified ZN stain.

Isosporiasis No presumptive clinical Chronic diarrhoea, often


diagnosis. profuse and watery, with
weight loss, ± abdominal pain,
nausea, vomiting. Isosporiasis
responds to high-dose co-
trimoxazole.

38
Clinical event Clinical diagnosis Definitive diagnosis

Cerebral or B cell non-Hodgkin No presumptive clinical Symptoms consistent with


lymphoma diagnosis. lymphoma: lymphadenopathy,
hepatosplenomegaly,
pancytopenia, besides other
nonspecific or organ-specific
symptoms. No response
clinically to antitoxoplasma or
anti-TB treatment.
CNS imaging: at least one
lesion with mass effect on
brain scan, and no response
to antitoxoplasma and anti-TB
treatment. Cytology. Histology.
Response to chemotherapy.

PML No presumptive clinical Progressive focal neurological


diagnosis. signs without headache or
fever. Cortical blindness and
cerebellar signs. Convulsions
are rare. MRI or CT scan

Acquired HIV-associated rectal Further information and


fistula, including rectovaginal evidence relating to this
fistula condition and its definition are
being sought. Case reports from
African countries suggest that it
is highly specific to HIV and that
the prognosis is poor. Clinical
features suggestive, exclusion of
other causes, faecal discharge
through the vagina or urethra,
or urine discharge through the
rectum in an HIV-infected child
usually following an episode of
diarrhoea.

39 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
Clinical event Clinical diagnosis Definitive diagnosis

HIV-associated nephropathy No presumptive clinical Further information and


diagnosis. evidence relating to this
condition and its definition
are being sought. Symptoms
and signs suggestive of renal
disease, with no other obvious
cause identified. Early morning
urine protein/creatinine ratio
of >200mg/mmol in absence
of a urinary tract infection
and absence of an axillary
temperature of 38.0 ºC. Renal
biopsy and histology.

HIV-associated cardiomyopathy No presumptive clinical Further information and


diagnosis. evidence relating to this
condition and its definition are
being sought. Exclusion of other
causes of congestive cardiac
failure. The left ventricle and
right ventricle are enlarged. The
end-diastolic and end-systolic
dimensions of the left or right
ventricle are increased (2 SDs
from the mean for body surface
area), with a reduced fractional
shortening and ejection
fraction (2 SDs from the mean).
Echocardiography check.

40
CLINICAL STAGING EVENTS AS A TOOL TO GUIDE
CLINICAL MANAGEMENT FOR INFANTS AND CHILDREN
( PRE-ART AND ART FOLLOW-UP CARE)

The same criteria for presumptive and definitive diagnosis apply

Clinical events pre-ART Action

Stage 1 May require cotrimoxazole

Stage 2 Requires cotrimoxazole

Stage 3 Requires cotrimoxazole if not already started


Or Consider ART
stage 4 Notification for surveillance purposes of first ever occurrence of
a stage 3 or 4 event.

Clinical events on ART Action

Stage 1 Currently not advised to discontinue cotrimoxazole in children


under 5 years.

New or recurrent : Check adherence, provide support


Stage 2 Treat and manage condition
or Should alert the provider to the possibility of poor adherence or
stage 3 failing response to treatment.

New or recurrent Check adherence, provide support


Stage 4 Treat and manage condition
Consider ART regimen switch
Suggests failure to respond to ART, possibly because of true
failure of the regimen and/or poor adherence.

41 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE AFRICAN REGION
KEY REFERENCES

1. http://www.who.int/hiv/strategic/surveillance/definitions/en/

2. http://www.who.int/3by5/publications/documents/arv_guidelines/en/

3. http://www.who.int/child-adolescent-health/publications/child_health/who_fch_
cah_00.1.htm

4. http://www.who.int/nut/documents/manage_severe_malnutrition_eng.pdf

5. Oral Manifestations of HIV in the Developing and Developed World. Proceedings


and abstracts of the 4th International Workshop on Oral Manifestations of HIV
Infection. Oral Dis. 2002; 8 Suppl 2:6-8.

6. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa:


a pooled analysis. The Lancet 2004; 364:1236-1243. Marie Louise Newell, Hoosen
Coovadia, Marjo Cortina-Borja, Nigel Rollins, Philippe Gaillard & Francois Dabis.
Available at :
http://www.thelancet.com/journals/lancet/article/PIIS0140673604171407/fulltext

7. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected


Zambian children (CHAP): a double-blind randomized placebo-controlled trial
C Chintu b, GJ Bhat b, AS Walker a, V Mulenga b, F Sinyinza b, K Lishimpi b, L
Farrelly , N Kaganson , A Zumla , SH Gillespie , AJ Nunn and DM Gibb on behalf of
the CHAP trial team. Available at:
http://www.thelancet.com/journals/lancet/article/PIIS0140673604174424/fulltext

8. PENTA guidelines for the use of antiretroviral therapy, 2004 M Sharland,


S Blanche, G Castelli, J Ramos and DM Gibb on behalf of the PENTA Steering
Committee. Available at http://www.ctu.mrc.ac.uk/penta/guidelin.pdf

9. US The Working Group on Antiretroviral Therapy and Medical Management of


HIV-Infected Children.Guidelines for the Use of Antiretroviral Agents in Pediatric
HIV Infection .March 24, 2005. Available at: http://aidsinfo.nih.gov/guidelines/
default_db2.asp?id=51

42
For more information, contact:

WORLD HEALTH ORGANIZATION


Department of HIV/AIDS
20, avenue Appia
CH-1211 Geneva 27
Switzerland
E-mail: hiv-aids@who.int
http://www.who.int/hiv/en